Effect of Methotrexate on Random Blood Sugar Level in Non-Diabetic Patients with Rheumatoid Arthritis

Volume 16 , Issue 1 , July 2026

Authors

Zainab Sarmak 1 ; Assistant professor Dr. Khalid 2

1 Department of Internal Medicine, College of Medicine, Hawler Medical University,Erbil, Iraq.

2 Department of Internal Medicine, College of Medicine, Hawler Medical University, Erbil, Iraq

DOI logo 10.17656/jsmc.10516

Keywords

Abstract

 Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease commonly treated with methotrexate (MTX). While MTX effectively controls disease activity, its effect on glucose metabolism, particularly random blood sugar (RBS), remains unclear. Objectives: To evaluate the impact of MTX therapy on RBS levels in non-diabetic patients with RA. Methods: Comparative cross-sectional study of 101 consecutively recruited non-diabetic adults with RA (HbA1c < 5.7%) attending a tertiary outpatient clinic (Rizgary Teaching Hospital, Erbil) from October 2024 to April 2025. Patients were classified by methotrexate (MTX) use and glucocorticoid (GC) exposure into four subgroups (MTX±GCs; non-MTX±GCs); MTX users were on a stable dose ≥ 6 months. Results: Of 101 patients, 52 used MTX and 49 did not. Subgroup sizes were: MTX/GC− (n=24; 23.76%), MTX/GC+ (n=28; 27.72%), no MTX/GC− (n=25; 24.75%), and GCs only (n=24; 23.76%). RBS was significantly lower in MTX users than non-users (103.4 ± 12.8 vs 121.3 ± 16.6 mg/dL; mean difference −17.9 mg/dL, 95% CI −22.9 to −12.9; p < 0.001). By subgroup, mean RBS followed a clear gradient—lowest in MTX/GC−, intermediate in MTX/GC+, and highest in GC-only (overall p < 0.001). HbA1c did not differ meaningfully between MTX users and non-users (5.29% vs 5.34%; p = 0.24). In multivariable models, MTX exposure remained independently associated with lower RBS (Model A β = −18.55 mg/dL, 95% CI −25.01 to −12.08; p < 0.001; Model B β = −14.80, 95% CI −23.00 to −6.60; p = 0.002). Notably, a higher GC dose was independently associated with higher RBS, whereas

References

  1. 1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. (2006);444(7121):860-867. https://doi.org/10.1038/nature05485.
  2. 2. Ormseth MJ, Swift LL, Fazio S, Linton MF, Chung CP, Raggi P, et al. Free fatty acids are associated with insulin resistance but not coronary artery atherosclerosis in rheumatoid arthritis. Atherosclerosis. (2011);219(2):869-874. https://doi.org/10.1016/j.atherosclerosis.2011.09.005
  3. 3. Hoes J, Van Der Goes M, Van Raalte D, Van Der Zijl N, Den Uyl D, Lems W, et al. Glucose tolerance, insulin sensitivity and β-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Annals of the rheumatic diseases. (2011);70(11):1887-1894. https://doi.org/10.1136/ard.2011.151464.
  4. 4. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes care. (2004);27(5):1047-1053. https://doi.org/10.2337/diacare.27.5.1047
  5. 5. Simard JF, Mittleman MA. Prevalent rheumatoid arthritis and diabetes among nhanes iii participants aged 60 and older. The Journal of rheumatology. (2007);34(3):469-473.
  6. 6. Solomon DH, Love TJ, Canning C, Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis. Annals of the rheumatic diseases. (2010);69(12):2114-2117. https://doi.org/10.1136/ard.2009.125476
  7. 7. Banerjee D, Ercikan-Abali E, Waltham M, Schnieders B, Hochhauser D, Li WW, et al. Molecular mechanisms of resistance to antifolates, a review. Acta Biochimica Polonica. (1995);42(4):457-464. https://doi.org/10.18388/abp.1995_4899.
  8. 8. Baghdadi LR, Woodman RJ, Shanahan EM, Wiese MD, Mangoni AA. Genetic polymorphism of the methotrexate transporter abcg2, blood pressure and markers of arterial function in patients with rheumatoid arthritis: Repeated cross-sectional study. Pharmacogenomics and Personalized Medicine. (2018);11(11):205-210. https://doi.org/10.2147/PGPM.S170557.
  9. 9. Baghdadi LR. Effect of methotrexate use on the development of type 2 diabetes in rheumatoid arthritis patients: A systematic review and meta-analysis. PLoS One. (2020);15(7):e0235637. https://doi.org/10.1371/journal.pone.0235637.
  10. 10. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5‐aminoimidazole‐4‐carboxamide ribonucleoside: A specific method for activating amp‐activated protein kinase in intact cells? European journal of biochemistry. (1995);229(2):558-565. https://doi.org/10.1111/j.1432-1033.1995.tb20498.x.
  11. 11. Viollet B, Foretz M, Guigas B, Horman S, Dentin R, Bertrand L, et al. Activation of amp‐activated protein kinase in the liver: A new strategy for the management of metabolic hepatic disorders. The Journal of physiology. (2006);574(1):41-53. https://doi.org/10.1113/jphysiol.2006.108506.
  12. 12. Hardie DG. Ampk: A target for drugs and natural products with effects on both diabetes and cancer. Diabetes. (2013);62(7):2164-2172. https://doi.org/10.2337/db13-0368.
  13. 13. Musi N, Goodyear L. Amp‐activated protein kinase and muscle glucose uptake. Acta Physiologica Scandinavica. (2003);178(4):337-345. https://doi.org/10.1046/j.1365-201X.2003.01168.x.
  14. 14. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of amp-activated protein kinase in mechanism of metformin action. The Journal of clinical investigation. (2001);108(8):1167-1174. https://doi.org/10.1172/JCI13505.
  15. 15. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. (2017);60(9):1577-1585. https://doi.org/10.1007/s00125-017-4342-z.
  16. 16. Pirkmajer S, Kulkarni SS, Tom RZ, Ross FA, Hawley SA, Hardie DG, et al. Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via ampk activation. Diabetes. (2015);64(2):360-369. https://doi.org/10.2337/db14-0508
  17. 17. Perdan-Pirkmajer K, Pirkmajer S, Thevis M, Thomas A, Praprotnik S, Hočevar A, et al. Methotrexate reduces hba1c concentration but does not produce chronic accumulation of zmp in patients with rheumatoid or psoriatic arthritis. Scandinavian journal of rheumatology. (2016);45(5):347-355. https://doi.org/10.3109/03009742.2015.1105290.
  18. 18. Mantravadi S, George M, Brensinger C, Du M, Baker JF, Ogdie A. Impact of tumor necrosis factor inhibitors and methotrexate on diabetes mellitus among patients with inflammatory arthritis. BMC rheumatology. (2020);4(1):39. https://doi.org/10.1186/s41927-2020-00138-3.
  19. 19. Baker JF, England BR, George M, Cannon G, Sauer B, Ogdie A, et al. Disease activity, cytokines, chemokines and the risk of incident diabetes in rheumatoid arthritis. Annals of the rheumatic diseases. (2021);80(5):566-572. https://doi.org/10.1136/annrheumdis-2020-219140.
  20. 20. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham Iii CO, et al. 2010 rheumatoid arthritis classification criteria: An american college of rheumatology/european league against rheumatism collaborative initiative. Arthritis & rheumatism. (2010);62(9):2569-2581. https://doi.org/10.1002/art.27584.
  21. 21. Elsayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. Improving care and promoting health in populations: Standards of care in diabetes—2023. Diabetes care. (2023);46(Supplement_1):S10-S18. https://doi.org/10.2337/dc23-S001.
  22. 22. Perdan-Pirkmajer K, Pirkmajer S, Hočevar A, Rotar Ž, Gašperšič N, Praprotnik S, et al. Ab0334 methotrexate reduces hba1c in non-diabetic patients with newly diagnosed rheumatoid arthritis or psoriatic arthritis. Annals of the Rheumatic Diseases. (2014);73:915. https://doi.org/10.1136/annrheumdis-2014-eular.2995.
  23. 23. Russo GT, Minutoli L, Bitto A, Altavilla D, Alessi E, Giandalia A, et al. Methotrexate increases skeletal muscle glut4 expression and improves metabolic control in experimental diabetes. Journal of Nutrition and Metabolism. (2012);2012(1):132056. https://doi.org/10.1155/2012/132056.
  24. 24. Tam HTX, Thuy LND, Vinh NM, Anh TN, Van BT. The combined use of metformin and methotrexate in psoriasis patients with metabolic syndrome. Dermatology Research and Practice. (2022);2022(1):9838867. https://doi.org/10.1155/2022/9838867.
  25. 25. Gisondi P, Cotena C, Tessari G, Girolomoni G. Anti–tumour necrosis factor‐α therapy increases body weight in patients with chronic plaque psoriasis: A retrospective cohort study. Journal of the European Academy of Dermatology and Venereology. (2008);22(3):341-344. https://doi.org/10.1111/j.1468-3083.2007.02429.x.
  26. 26. Riedinger C, Mendler M, Schlotterer A, Fleming T, Okun J, Hammes H-P, et al. High-glucose toxicity is mediated by aicar-transformylase/imp cyclohydrolase and mitigated by amp-activated protein kinase in caenorhabditis elegans. Journal of Biological Chemistry. (2018);293(13):4845-4859. https://doi.org/10.1074/jbc.M117.805879.
  27. 27. Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint bone spine. (2019);86(3):301-307. https://doi.org/10.1016/j.jbspin.2018.07.004.
  28. 28. Yano N, Zhang L, Wei D, Dubielecka PM, Wei L, Zhuang S, et al. Irisin counteracts high glucose and fatty acid-induced cytotoxicity by preserving the ampk-insulin receptor signaling axis in c2c12 myoblasts. American Journal of Physiology-Endocrinology and Metabolism. (2020);318(5):791-805. https://doi.org/10.1152/ajpendo.00219.2019.
  29. 29. Wu JJ, Rowan CG, Bebchuk JD, Anthony MS. No association between tnf inhibitor and methotrexate therapy versus methotrexate in changes in hemoglobin a1c and fasting glucose among psoriasis, psoriatic arthritis, and rheumatoid arthritis patients. Journal of drugs in dermatology: JDD. (2015);14(2):159-166.
  30. 30. Dehpouri T, Rokni GR, Narenjbon NA, Goldust M, Yamauchi PS, Wollina U, et al. Evaluation of the glycemic effect of methotrexate in psoriatic arthritis patients with metabolic syndrome: A pilot study. Dermatology reports. (2019);11(1):7965. https://doi.org/10.4081/dr.2019.7965.
  31. 31. Su Y-J, Chen H-M, Chan T-M, Cheng T-T, Yu S-F, Chen J-F, et al. Disease-modifying anti-rheumatic drugs associated with different diabetes risks in patients with rheumatoid arthritis. RMD open. (2023);9(3):e003045. https://doi.org/10.1136/rmdopen-2023-003045.
  32. 32. Dessein PH, Joffe BI, Stanwix AE, Christian BF, Veller M. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. The Journal of Rheumatology. (2004);31(5):867-874.
  33. 33. Tian Z, Mclaughlin J, Verma A, Chinoy H, Heald AH. The relationship between rheumatoid arthritis and diabetes mellitus: A systematic review and meta-analysis. Cardiovascular endocrinology & metabolism. (2021);10(2):125-131. https://doi.org/10.1097/XCE.0000000000000244.
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